Arrhythmogenic right ventricular cardiomyopathy (ARVC, previously called “dysplasia”) is a rare genetic heart disease caused by structural irregularities in right ventricular (RV) myocytes and the presentation of ventricular arrhythmias. The prevalence in the general population varies between 1:1000 to 1:10000 depending on geographical region. (1-3) The disease results in the progressive replacement of myocardial tissue in the RV with fatty fibrous tissue that starts at the epicardium and spreads over the middle of the myocardium to the whole RV wall. Such progression can cause ventricular aneurysms and significant changes to the capacity of transferring normal impulses in the right heart. Degeneration of myocardial tissue can spread to the left ventricle (LV) in later stages of the disease, although in rare cases the LV can be the primary localization. A certain amount of fatty tissue can be found in a healthy RV, increasing with age and body mass. (3, 4) Ventricular arrhythmias in this disease can manifest as ventricular extrasystole (VES), any form of ventricular tachycardia (VT), and finally as ventricular fibrillation (VF). (2)
The natural course of ARVC includes four clinicopathological stages. 1. The subclinical stage, associated with only microscopical ultrastructural changes in the myocardium, where sudden cardiac death can be the first sign of the disease. 2. The symptomatic stage, in which the manifestation of left bundle branch block (LBBB) morphology arrhythmia is very common, along with numerous other symptoms such as palpitation, syncope, and sudden cardiac death. Only in this stage is it possible to demonstrate the presence of the disease using imaging methods. 3. Progressive RV dysfunction, often also associated with LV involvement and failure. 4. Global RV dilatation and biventricular involvement leading to heart failure. (1, 5)
ARVC is generally an autosomal dominant hereditary disease, although there are also autosomal recessive syndromes related to it. One of them is Naxos disease, where a mutation of the plakoglobin gene leads to structural disorders of desmosomes and adhesion molecules, which manifest as palmoplantar keratoderma and woolly hair. (2) The most important autosomal dominant mutations are related to desmosomes and their function. Today there are more than 140 different mutations that can influence the development of ARVC. The majority of the ultrastructural changes found in ARVC are related to the remodeling of intercalated discs with incorrect positioning and the reduction of the number of desmosomes in the RV myocardium. Since the main function of desmosomes is maintaining the normal function of gap junctions, intercellular signalization problems occur, eventually leading to disorders in cell growth, differentiation, development, and normal conduction of electrical impulses. (2, 3) Cases of multiple gene mutations in the same person have also been described, where the disease manifested at an earlier age with more severe arrhythmias. The largest number of mutations are related to the genes for plakophilin-2 and desmoglein-2, both responsible for desmosome function. (1, 6) The prevalence of most gene mutations that can be caused by ARVC is the same in men and women, other than for plakophilin, but from a phenotype perspective the disease severity is predominantly more severe in men, possibly due to larger volumes and poorer RV function. (7) The greatest number of RV changes is mostly related to the lower back part of the RV inflow tract (RVIT) beside the tricuspid valve and forward ventricular infundibulum, but changes have also been found in the apical part of the RV, and these three localizations are jointly called the triangle of dysplasia (Figure 1). (2, 8) Degeneration and death of myocytes and their replacement with fatty tissue are the result of disordered desmosome function, as the key factor in the maintenance of myocyte function, which eventually leads to inflammation and formation of a fibrous scar that is subsequently replaced with fatty tissue. All these changes are especially significant with severe RV load that manifests physiologically during repeated strenuous physical activity. (1, 2) Functionally, focal thinning of RV free wall results in regional contraction irregularities, systolic and diastolic RV dysfunction, ventricular aneurysms, and the dilatation and hypokinesis of a part of the ventricular wall. It is especially interesting that the interventricular septum is mostly spared any changes. (5)
Disease symptoms are extremely rare below age 12 and above age 60. Median age for symptom manifestation is usually 36±14 years of age, with symptoms being 3 times more common in men compared with women. It presents very variable symptoms, including palpitation, syncope, chest pain, dyspnea, and sudden cardiac death (SCD). (4, 6) ARVC is the leading cause of SCD in persons younger than 40. Three quarters of SCD episodes take place during routine daily activities, 10% during the perioperative period, and only 3.5% during strenuous physical activity. (4)
A completely normal 12-lead electrocardiogram (ECG) result can be observed in about 12% of persons with ARVC, but changes in the ECG results do not demonstrate the presence of ARVC. Prolonged terminal activation duration is observed in approximately 5-20% of cases and presents as a prolongation of the S wave in V1-V3 leads, with the longest value from the bottom of the S wave to the end of the whole QRS complex in an amount exceeding 55 ms with r’ omission. The second characteristic is the appearance of a complete or incomplete right bundle branch block (RBBB) that indicates disordered conductivity of the Purkinje fibers. It is important to eliminate other states that can lead to the same phenomenon in ECG results, which include athletic heart, pectus excavatum, and improper positioning of the V1 and V2 lead electrodes on the thorax. More dangerous states that can present with the same characteristics are RV enlargement, LV pre-excitation, hypercalcemia, and Brugada type 2. (9) Presence of the epsilon wave is a characteristic that is relatively specific to ARVC. Unfortunately, it has been found in only 10-35% of ARVC cases. It is caused by subsequent excitatory low-amplitude potentials predominantly from the free RV wall and the outflow tract of the right ventricle (RVOT) which appear within the ST segment without elevation or depression in V1-V3 leads. (2, 9) The fourth phenomenon in the ECG is the regional delay of the normal ventricular depolarization, presenting as a fragmentation of the QRS complex (fQRS) in the shape of a comma, deceleration, and the presence of ≥4 spikes within the QRS complex. Such a phenomenon can also be found in many other diseases such as Brugada syndrome and cardiomyopathies. Asymmetrical inverted T waves in the V1 and V2 leads in persons above the age of 14 can indicate ARVC, and are more common than epsilon waves. Especially significant is a very deep negative T wave (>3 mm) in the V1 lead. (9) All the above mentioned changes are shown in Figure 2.
Undiagnosed cases with family history positive for ARVC have a higher risk of developing arrhythmias. Consequently, observing T wave inversion in the V1 and V2 leads after 14 years of age and a total number >1000 VES / 24 hours are key in establishing the diagnosis in the members of such families. Due to low overall sensitivity and specificity of ECG as a test for ARVC, many cases still remain undiagnosed even today, and are usually discovered during the evaluation of malignant arrhythmias or, unfortunately, post-mortem. (6) Despite that, VF is less common in older patients with longer disease duration, under the assumption that a higher ratio of fibrous tissue facilitates the development of hemodynamically stable VT. (3)
Establishing the diagnosis
The first diagnostic criteria were developed in 1994 under the name Task Force Criteria (TFC). They were revised in 2010 to improve their sensitivity and specificity, but the criteria for establishing the diagnosis remained the same. Accordingly, establishing the diagnosis of ARVC requires the fulfillment of 2 major criteria, 1 major and 2 minor criteria, or 4 minor criteria. The revision from 2010 encompasses 6 main categories shown in Table 1. (2, 10) Imaging methods have a very important role in the TFC criteria. The most important of them is RV angiography due to its high specificity, but echocardiography and cardiac magnetic resonance (CMR) have now almost completely replaced it. Nevertheless, the diagnosis still cannot be established on the basis of one finding from one of these tests, but only with a combination of them. (1-3) CMR has also proven to be excellent for early disease detection because it is excellent in recognizing areas of regional and diastolic ventricular dysfunction, and with the addition of a gadolinium contrast medium it can also recognize areas of intramyocardial fibrosis. Unfortunately, the sensitivity of CMR in later stages of the disease is lower. (3) Biopsies should be performed on the RV free wall, since the disease usually spares the RV septum. Positive pathohistological biopsy findings are also not sufficient to establish the final diagnosis, but are instead classified as a major criterion in the TFC. Three-dimensional electroanatomical mapping (TEM) is also an important test that can reveal areas of low voltage areas. Such areas can represent the replacement of myocardial tissues with fibrous and fatty tissues, and the test is very helpful in differentiating inflammatory cardiomyopathy and idiopathic tachycardia from the RVIT, which are diseases that can have a similar clinical picture as ARVC. (2, 3) The RV diameter, although not present in the TFC, has shown itself to be a good risk indicator for the development of arrhythmias. A study by Leren et al. (11) clearly showed significantly increased risk of arrhythmia if the RV diameter is ≥41 mm. Furthermore, non-homogenous RV contraction, which can appear on the ECG as a mechanical potential dispersion of ≥37 ms, is associated with the appearance of severe arrhythmias originating in the RV.
There are numerous states that can cause very similar symptoms as ARVC. Idiopathic RVOT arrhythmia is definitely the most common diagnostic problem regarding this disease. Attention should also be paid to ECG results for athletic heart syndrome, which can obscure the true diagnosis of ARVC (Figure 3, B, C). Every VT with a localized free wall mobility disorder with or without inflammation can be caused by cardiac sarcoidosis or myocarditis. Differentiating these diseases is possible only with pathohistological confirmation, i.e. heart biopsy results. A less specific finding in sarcoidosis is the presence of conducting system disease with the prolongation of the PR interval and AV block, which almost never occurs in ARVC. Since low voltage QRS complexes can be observed even in later stages of ARVC, family history plays the largest role in the evaluation of myocarditis. If it is negative, the likelihood of myocarditis is increased. (4)
Uhl’s anomaly is a very rare RV disorder characterized by a lack of RV myocardium with apposition of the endocardium and epicardium. Another congenital anomaly is the aforementioned pectus excavatum, which changes the ECG due to its anatomical characteristics (Figure 3, D). (3, 4)
Differentiating ARVC from dilated cardiomyopathy affecting the RV can be very difficult in later stages of the disease with LV ejection fraction <50%, but VT and SCD are extremely rare in dilated cardiomyopathy and their presence increases the likelihood of ARVC. Although this is rare, Brugada syndrome with type 2 changes can be diagnosed instead of ARVC in the ECG (Figure 3, G). Typical ST-segment elevation in the shape of type 1 Brugada syndrome is almost never seen in ARVC. Hypertrophic cardiomyopathy should also be mentioned as a rare, but significant problem in the differential diagnosis of ARVC (Figure 3, F). (4) In spite of all the diagnostic methods and algorithms, more than 50% of true ARVC are still incorrectly diagnosed. (2, 4, 9)
The influence of physical activity on arrhythmogenic right ventricular cardiomyopathy
In sports, ARVC is afforded special attention. Kirchof et al. (12) used transgenic plakoglobin-deficient mice to demonstrate that activities requiring great endurance are associated with RV enlargement, slowed conduction to the RV, and the appearance of an increased number of arrhythmias of RV free wall origin. Fabritz et al. (13) later demonstrated that sparing in such mice prevents the development of the ARVC phenotype. None of these studies found evidence of fibrous or fatty myocardial changes in the mice. James et al. (14) were the first to demonstrate the influence of physical activity on ARVC progression in humans. The study presents very significant discoveries for understanding the nature of ARVC. The most important of these are: 1. The symptomatic phase of the disease takes place very early in the lives of very active athletes who are gene carriers for ARVC, coupled with poorer CMR findings; 2. The duration and type of activity determines ARVC development time; 3. Longtime active athletes who have been active for many years have a much poorer prognosis and outcomes for ventricular arrhythmias; 4. Longtime athletes who continue engaging in sports after ARVC diagnosis have poorer survival compared with those who stopped engaging in the same sport after the diagnosis was established.
An extremely important discovery corroborating the theories above is the evidence showing that components of the intercalated disc (including desmosomes) start connecting only around 1 year of age, and their maturation and movement continue until puberty. Accordingly, excessive amounts of strenuous physical activity of only 4 hours per week in childhood can significantly modify the structure of the RV, especially in carriers of mutations that are possible causes of ARVC. This phenomenon is explained by reduced permeability in the pulmonary circulation that, mediated by increased RV ejection fraction in strenuous physical activity, causes extremely elevated pressure in pulmonary circulation. In such cases, RV load can be 170% larger compared with RV load at rest. In such persons, repeated damage to the myocardium can in some cases lead to the replacement of myocytes with fibrous or fatty tissue and eventually the development of potentially lethal arrhythmia. Although it is extremely rare, is it possible for these changes to take place even in well-trained athletes with no positive family history or findings of mutations that cause ARVC. (1) For asymptomatic athletes with positive family history, detailed and frequent monitoring of their state of health from an early age is recommended. Such persons are forbidden to participate in strenuous physical activities more than several months at a time and forbidden to participate at all if signs of the disease appear; choosing a non-strenuous sport is recommended. (1, 4)
The decision to start the treatment of arrhythmias originating in the RV, of which VES are the most common, is made based on the symptoms of the arrhythmia and whether or not there is LV dysfunction. As a rule, if VES is not coupled with myocardial ischemia or concomitant structural heart disease, VES is considered a benign state. A finding of more than 20% of VES during 24-hour Holter monitoring is associated with long-term LV dilation and dysfunction with possible cardiomyopathy, so radiofrequency ablation (RFA) of the foci of the symptomatic arrhythmia is recommended. Another possible approach is conservative treatment, where the main goal is to reduce the symptoms caused by arrhythmias while monitoring the influence of medication of the function of the sinoatrial node, atrioventricular node, QT-interval duration, and liver and kidney function. (15) Special caution and a careful approach is warranted by the treatment of ARVC and Brugada syndrome, since their course is less favorable than idiopathic arrhythmias originating in the RV.
The main goal of the treatment of this disease is the prevention of SCD. Consequently, educating patients with ARVC is of paramount importance and is performed with the goal of limiting physical activity and changing the patient’s lifestyle. (8) Patients with ARVC who are young and did not present with syncope, heart failure, negative T wave in the precordial leads excluding the V1 lead, VT, and >20% VES during 24-hour Holter monitoring usually do not have a high risk for the development of malignant arrhythmias and do not require specific treatment with antiarrhythmic drugs. In others, prevention of the development of malignant arrhythmias and SCD is most effectively achieved by sotalol (68% effectiveness). However, individual studies indicate that beta-blockers have neither a protective nor a harmful effect in the treatment of ARVC, making amiodarone the most effective medication. (2, 5) Other medications that can be used for the treatment of this disease, either singly or in combination with those listed above, are antiarrhythmic drugs of the Ia class (procainamide), Ib class (mexiletine), and the Ic class (flecainide and propafenone) that have been used with varying success. (8)
Prevention of sudden cardiac death with an implantable cardioverter defibrillator
An implantable cardioverter defibrillator (ICD) is a device that registers the appearance of malignant arrhythmia and defibrillates it in a timely manner. In patients with ARVC and Brugada syndrome there is a high risk for development of malignant arrhythmias in a certain phase of the natural course of the disease. It is important to emphasize that individually ascertaining that risk and whether an ICD is really necessary in a given patient is a crucial aspect of ICD application. (8)
Bearing in mind that every manifestation of malignant arrhythmia can end in death, a study by Corrado et al. (16) demonstrated that the real survival of patients with ARVC using an ICD was 99% in 12-month follow-up, 98% in 24-month follow-up, and 96% in 36-month follow-up. In comparison, patient survival in these follow-up intervals with no ICD would be 88%, 79%, and 72%, respectively, which directly demonstrates that ICD saves 23% of patients from SCD. Despite this, however, prophylactic use of ICDs in asymptomatic patients or persons carrying the ARVC gene is currently not recommended because the total amount of complications after ICD implantation is greater than the real benefits of the ICD. (3) The total number of complications after ICD implantation in patients with ARVC is higher than in other diseases for which ICDs are indicated. (2)
Ablation for arrhythmias originating in the right ventricular outflow tract
The main absolute indication for RVOT ablation is the presence of frequent arrhythmias with or without symptoms in patients with structural heart disease. Other indications include poor response to medication treatment and patient choice. (15)
RF ablation of this focus effectively reduces the VES number in 24 hour Holter monitoring, significantly reduces or eliminates all symptoms of arrhythmia, improves quality of life, and improves cardiomyopathy status and LV ejection fraction. (15)
The successfulness of RF ablation in ARVC is significantly lower due to the appearance of new foci caused by fibrous and/or fatty tissue changes in the myocardium, whose histological characteristics permit circus-like re-entry arrhythmias. Arrhythmias with such foci present different QRS complexes and have been observed in 40-60% of patients with ARVC during long-term follow-up after ablation. (2, 5, 17, 18) Ablation of arrhythmogenic RV foci in ARVC is therefore only a palliative treatment method and does not reduce the risk of SCD in the long term. (6)
Congestive heart failure caused by expansion of fibrous fatty tissue to the LV in the progression of ARVC can be cured only by orthotropic heart transplantation. Transplantation must be considered as a treatment option in case of refractory heart failure with or without uncontrolled arrhythmias. (5, 19)